We will develop methods and parallel flow instrumentation for high-throughput, high- content, cell-based screening, for phenotyping and manipulation of small rare-cell fractions, and for multiplexed expression analysis from 1-100 cells in flow. We will provide means for combinatorial scaling of mechanistic and small-molecule studies of protein misfolding disease, particularly neurodegenerative diseases such as Parkinson's (model organism: yeast). And for high-content cytometry studies with (rare) primary hematopoietic stem cells (mouse). PUBLIC HEALTH RELEVANCE: This program would develop new instrumentation and methods for cell-based high- throughput, high-content screening (HCS). The program addresses bottlenecks that severely limit HCS for (i) scale-up to drug discovery, (ii) for handling of small samples of highly heterogeneous primary cell types; (iii) for finding rare cells (e.g. finding pluripotent cells for cancer diagnostics) and, (iv) image-based sorting/enrichment.